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| | <StructureSection load='5wqi' size='340' side='right'caption='[[5wqi]], [[Resolution|resolution]] 1.90Å' scene=''> | | <StructureSection load='5wqi' size='340' side='right'caption='[[5wqi]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5wqi]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WQI OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5WQI FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5wqi]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Aspergillus_terreus_NIH2624 Aspergillus terreus NIH2624]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WQI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5WQI FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7X0:(1R,2S,4aS,4bS,8aS,10S,10aS)-2-[(2S)-3-methoxy-2-methyl-2-oxidanyl-3-oxidanylidene-propanoyl]-2,3,4b,8,8,10a-hexamethyl-10-oxidanyl-7,9-bis(oxidanylidene)-1,4a,5,6,8a,10-hexahydrophenanthrene-1-carboxylic+acid'>7X0</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.899Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5wqf|5wqf]], [[5wqg|5wqg]], [[5wqh|5wqh]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7X0:(1R,2S,4aS,4bS,8aS,10S,10aS)-2-[(2S)-3-methoxy-2-methyl-2-oxidanyl-3-oxidanylidene-propanoyl]-2,3,4b,8,8,10a-hexamethyl-10-oxidanyl-7,9-bis(oxidanylidene)-1,4a,5,6,8a,10-hexahydrophenanthrene-1-carboxylic+acid'>7X0</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5wqi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wqi OCA], [http://pdbe.org/5wqi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wqi RCSB], [http://www.ebi.ac.uk/pdbsum/5wqi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wqi ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5wqi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wqi OCA], [https://pdbe.org/5wqi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5wqi RCSB], [https://www.ebi.ac.uk/pdbsum/5wqi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5wqi ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/TRT14_ASPTN TRT14_ASPTN]] Isomerase; part of the gene cluster that mediates the biosynthesis of terretonin, a fungal meroterpenoid that acts as a mycotoxin (PubMed:22549923, PubMed:23116177, PubMed:25671343). The first step of the pathway is the synthesis of 3,5-dimethylorsellinic acid (DMOA) by the polyketide synthase trt4 (PubMed:22549923, PubMed:23116177). DMOA is then prenylated into farnesyl-DMOA by the polyprenyl transferase trt2 (PubMed:22549923, PubMed:22782788, PubMed:23116177). Methylation by the methyltransferase trt5 then leads to farnesyl-DMOA methyl ester which is further subject to epoxidation by the FAD-dependent monooxygenase trt8 to yield epoxyfarnesyl-DMOA methyl ester (PubMed:22549923, PubMed:22782788, PubMed:23116177). Cyclization of epoxyfarnesyl-DMOA methyl ester by the terpene cyclase trt1 leads to a tetracycle intermediate which is in turn converted to preterretonin (PubMed:22549923, PubMed:22782788, PubMed:23116177). Dehydrogenase trt9 comes next to transform preterretonin to preterrenoid (PubMed:22549923, PubMed:23116177). The FAD-dependent monooxygenase trt3 is then required for the C-hydroxylation at C16 of preterrenoid to yield terrenoid (PubMed:22549923, PubMed:23116177). The cytochrome P450 trt6 catalyzes three successive oxidations to transform terrenoid into an unstable intermediate, which then undergoes the D-ring expansion and unusual rearrangement of the methoxy group to afford the core skeleton of terretonin (PubMed:25671343). This unprecedented rearrangement is catalyzed by the isomerase trt14 (PubMed:25671343). Finally, the nonheme iron-dependent dioxygenase trt7 accomplishes the last two oxidation reactions steps to complete the biosynthesis of terretonin (PubMed:25671343). Terretonin C is produced via spontaneous decarboxylation of the terretonin precursor (PubMed:23116177). Another shunt product of the terretonin biosynthesis is dihydrofarnesyl-DMOA, derived from epoxyfarnesyl-DMOA through hydrolysis of the epoxide (PubMed:22549923, PubMed:22782788, PubMed:23116177).<ref>PMID:22549923</ref> <ref>PMID:22782788</ref> <ref>PMID:23116177</ref> <ref>PMID:25671343</ref> | + | [https://www.uniprot.org/uniprot/TRT14_ASPTN TRT14_ASPTN] Isomerase; part of the gene cluster that mediates the biosynthesis of terretonin, a fungal meroterpenoid that acts as a mycotoxin (PubMed:22549923, PubMed:23116177, PubMed:25671343). The first step of the pathway is the synthesis of 3,5-dimethylorsellinic acid (DMOA) by the polyketide synthase trt4 (PubMed:22549923, PubMed:23116177). DMOA is then prenylated into farnesyl-DMOA by the polyprenyl transferase trt2 (PubMed:22549923, PubMed:22782788, PubMed:23116177). Methylation by the methyltransferase trt5 then leads to farnesyl-DMOA methyl ester which is further subject to epoxidation by the FAD-dependent monooxygenase trt8 to yield epoxyfarnesyl-DMOA methyl ester (PubMed:22549923, PubMed:22782788, PubMed:23116177). Cyclization of epoxyfarnesyl-DMOA methyl ester by the terpene cyclase trt1 leads to a tetracycle intermediate which is in turn converted to preterretonin (PubMed:22549923, PubMed:22782788, PubMed:23116177). Dehydrogenase trt9 comes next to transform preterretonin to preterrenoid (PubMed:22549923, PubMed:23116177). The FAD-dependent monooxygenase trt3 is then required for the C-hydroxylation at C16 of preterrenoid to yield terrenoid (PubMed:22549923, PubMed:23116177). The cytochrome P450 trt6 catalyzes three successive oxidations to transform terrenoid into an unstable intermediate, which then undergoes the D-ring expansion and unusual rearrangement of the methoxy group to afford the core skeleton of terretonin (PubMed:25671343). This unprecedented rearrangement is catalyzed by the isomerase trt14 (PubMed:25671343). Finally, the nonheme iron-dependent dioxygenase trt7 accomplishes the last two oxidation reactions steps to complete the biosynthesis of terretonin (PubMed:25671343). Terretonin C is produced via spontaneous decarboxylation of the terretonin precursor (PubMed:23116177). Another shunt product of the terretonin biosynthesis is dihydrofarnesyl-DMOA, derived from epoxyfarnesyl-DMOA through hydrolysis of the epoxide (PubMed:22549923, PubMed:22782788, PubMed:23116177).<ref>PMID:22549923</ref> <ref>PMID:22782788</ref> <ref>PMID:23116177</ref> <ref>PMID:25671343</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Aspergillus terreus NIH2624]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Abe, I]] | + | [[Category: Abe I]] |
| - | [[Category: Matsuda, Y]] | + | [[Category: Matsuda Y]] |
| - | [[Category: Mori, T]] | + | [[Category: Mori T]] |
| - | [[Category: Isomerase]]
| + | |
| - | [[Category: Meroterpenoid]]
| + | |
| - | [[Category: Terretonin]]
| + | |
| Structural highlights
Function
TRT14_ASPTN Isomerase; part of the gene cluster that mediates the biosynthesis of terretonin, a fungal meroterpenoid that acts as a mycotoxin (PubMed:22549923, PubMed:23116177, PubMed:25671343). The first step of the pathway is the synthesis of 3,5-dimethylorsellinic acid (DMOA) by the polyketide synthase trt4 (PubMed:22549923, PubMed:23116177). DMOA is then prenylated into farnesyl-DMOA by the polyprenyl transferase trt2 (PubMed:22549923, PubMed:22782788, PubMed:23116177). Methylation by the methyltransferase trt5 then leads to farnesyl-DMOA methyl ester which is further subject to epoxidation by the FAD-dependent monooxygenase trt8 to yield epoxyfarnesyl-DMOA methyl ester (PubMed:22549923, PubMed:22782788, PubMed:23116177). Cyclization of epoxyfarnesyl-DMOA methyl ester by the terpene cyclase trt1 leads to a tetracycle intermediate which is in turn converted to preterretonin (PubMed:22549923, PubMed:22782788, PubMed:23116177). Dehydrogenase trt9 comes next to transform preterretonin to preterrenoid (PubMed:22549923, PubMed:23116177). The FAD-dependent monooxygenase trt3 is then required for the C-hydroxylation at C16 of preterrenoid to yield terrenoid (PubMed:22549923, PubMed:23116177). The cytochrome P450 trt6 catalyzes three successive oxidations to transform terrenoid into an unstable intermediate, which then undergoes the D-ring expansion and unusual rearrangement of the methoxy group to afford the core skeleton of terretonin (PubMed:25671343). This unprecedented rearrangement is catalyzed by the isomerase trt14 (PubMed:25671343). Finally, the nonheme iron-dependent dioxygenase trt7 accomplishes the last two oxidation reactions steps to complete the biosynthesis of terretonin (PubMed:25671343). Terretonin C is produced via spontaneous decarboxylation of the terretonin precursor (PubMed:23116177). Another shunt product of the terretonin biosynthesis is dihydrofarnesyl-DMOA, derived from epoxyfarnesyl-DMOA through hydrolysis of the epoxide (PubMed:22549923, PubMed:22782788, PubMed:23116177).[1] [2] [3] [4]
Publication Abstract from PubMed
Trt14 from Aspergillus terreus is involved in unusual skeletal reconstruction during the biosynthesis of the fungal meroterpenoid terretonin. Detailed in vitro characterization revealed that this novel multifunctional enzyme catalyzes not only the D-ring expansion via intramolecular methoxy rearrangement, but also the hydrolysis of the expanded D-ring. The X-ray crystal structures of Trt14, in complex with substrate or product, and two Trt14 homologs, AusH and PrhC from Aspergillus nidulans and Penicillium brasilianum, respectively, indicated similar overall structures to those of the NTF2-like superfamily of enzymes, despite lacking sequence and functional similarities. Moreover, we gained structural insight into the mechanism of the Trt14-catalyzed ring reconstruction from the in-crystal enzyme reaction and site-directed mutagenesis to show that this reaction involves sequential ester bond cleavage and formation. Structural comparison of Trt14 and its homologs suggests that the enzymes in this new superfamily employ similar acid-base chemistry to diversify the molecular architecture of fungal meroterpenoids.
Molecular basis for the unusual ring reconstruction in fungal meroterpenoid biogenesis.,Mori T, Iwabuchi T, Hoshino S, Wang H, Matsuda Y, Abe I Nat Chem Biol. 2017 Oct;13(10):1066-1073. doi: 10.1038/nchembio.2443. Epub 2017, Jul 31. PMID:28759016[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Itoh T, Tokunaga K, Radhakrishnan EK, Fujii I, Abe I, Ebizuka Y, Kushiro T. Identification of a key prenyltransferase involved in biosynthesis of the most abundant fungal meroterpenoids derived from 3,5-dimethylorsellinic acid. Chembiochem. 2012 May 29;13(8):1132-5. doi: 10.1002/cbic.201200124. Epub 2012 Apr, 30. PMID:22549923 doi:http://dx.doi.org/10.1002/cbic.201200124
- ↑ Matsuda Y, Awakawa T, Itoh T, Wakimoto T, Kushiro T, Fujii I, Ebizuka Y, Abe I. Terretonin biosynthesis requires methylation as essential step for cyclization. Chembiochem. 2012 Aug 13;13(12):1738-41. doi: 10.1002/cbic.201200369. Epub 2012, Jul 10. PMID:22782788 doi:http://dx.doi.org/10.1002/cbic.201200369
- ↑ Guo CJ, Knox BP, Chiang YM, Lo HC, Sanchez JF, Lee KH, Oakley BR, Bruno KS, Wang CC. Molecular genetic characterization of a cluster in A. terreus for biosynthesis of the meroterpenoid terretonin. Org Lett. 2012 Nov 16;14(22):5684-7. doi: 10.1021/ol302682z. Epub 2012 Nov 1. PMID:23116177 doi:http://dx.doi.org/10.1021/ol302682z
- ↑ Matsuda Y, Iwabuchi T, Wakimoto T, Awakawa T, Abe I. Uncovering the unusual D-ring construction in terretonin biosynthesis by collaboration of a multifunctional cytochrome P450 and a unique isomerase. J Am Chem Soc. 2015 Mar 11;137(9):3393-401. doi: 10.1021/jacs.5b00570. Epub 2015 , Feb 25. PMID:25671343 doi:http://dx.doi.org/10.1021/jacs.5b00570
- ↑ Mori T, Iwabuchi T, Hoshino S, Wang H, Matsuda Y, Abe I. Molecular basis for the unusual ring reconstruction in fungal meroterpenoid biogenesis. Nat Chem Biol. 2017 Oct;13(10):1066-1073. doi: 10.1038/nchembio.2443. Epub 2017, Jul 31. PMID:28759016 doi:http://dx.doi.org/10.1038/nchembio.2443
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